Alpha 1 and alpha 2 adrenergic receptors serve numerous functions throughout the central and peripheral nervous systems and, as such, have served as useful targets for the development of drugs to treat of a number of disorders such as narcolepsy, intractable pain, hypertension, benign prostatic hyperplasia and glaucoma. Unfortunately, many alpha adrenergic drugs that have been developed have had significant side-effects which have limited their therapeutic usefulness. The recent identification of six alpha adrenergic receptor subtypes (alpha1a, alpha1b, alpha1d, alpha2a, alpha2b, alpha2c) may allow for the discovery of improved therapeutic alpha adrenergic agents with improved efficacy and fewer side-effects. The proposed research involves the design and synthesis of subtype- selective alpha adrenergic irreversible ligands, photoaffinity ligands and radioligands. These tool compounds will be characterized using cloned human, rat and dog alpha adrenergic receptors and used to study the distribution and functional relevance of alpha 1 and alpha 2 subtypes in intact tissues. In addition, these tool ligands will also be used in structure-function studies using mutated and chimeric receptors to study ligand-receptor interactions. These studies should provide valuable information which will aid the discovery of novel subtype-selective adrenergic drugs. PROPOSED COMMERCIAL APPLICATION: This research will lead to the development of novel, subtype-selective drugs which target alpha adrenergic receptors and may be useful for the treatment of diseases such as narcolepsy, intractable pain, hypertension, begin prostatic hyperplasia, urinary incontinence and glaucoma with fewer side-effects than existing therapeutic agents.